Appropriate fetal growth and development is dependent upon a multitude of hormonal, genetic, environmental, and nutritional factors. Survival of the fetus is dependent on the ability of the placenta to maintain a balance between the adequate supply of nutrients and simultaneous disposal of waste materials to the maternal circulation. Hence, appropriate and rapid placental responses to insults in either the maternal or fetal compartments will significantly impact the outcome of the pregnancy. Acute fetal insult in the rodent results in changes in placental expression of various nutrient transporters, components of the insulin-like growth factor (IGF) signaling pathway, and the organization of a population of cells termed glycogen cells. Glycogen cells are an important indicator of normal placental development, and are frequently disrupted in pregnancies complicated by diabetes, preeclampsia and intrauterine growth retardation. Both IGF-I and IGF-II are known to have effects on fetal growth. IGF-II in addition has also been shown to play a significant role in placental growth, with IGF-II null animals developing small placentas with a dramatic depletion in glycogen cells. IGFs circulate bound to a family of insulin-like growth factor binding proteins (IGFBPs) which limit/modify their actions, along with displaying IGF-independent effects, unique to each IGFBP. The expression of one of these binding proteins, IGFBP-2 is remarkable, in that it is highly complementary to the expression of IGF-II throughout gestation. In this project we propose to investigate the effects of fetal insult on placental gene expression, and specifically the result of disruptions in the normal IGF-II - IGFBP-2 expression patterns in placental development. In Aim 1 we analyze changes in gene expression following fetal insult/death. Aim 2 focuses on placental development in animals with over expression of IGF-II and IGFBP-2. In Aim 3 the influence of IGF-II on the differentiation of the trophoblast cell lineage is examined. The proposed research utilizes both in vitro and in vivo strategies. Data derived from these experiments will add to our understanding of the factors involved in placental development, as well as of the role of the fetus in regulating placental metabolism to compensate for adverse fetal and maternal stimuli. This research will contribute to our knowledge of the etiology and pathogenesis of intrauterine growth retardation and perinatal morbidity and mortality.